The IGF (insulin-like growth factor) system consists of a well characterized set of polypeptides that cells use to communicate with their physiologic environment. This system comprises two cell-surface receptors (IGF1R and IGF2R), two peptidic ligands (IGF-I and IGF-II), a family of six high-affinity IGF binding proteins (IGFBP-1 to 6), as well as associated IGFBP-degrading enzymes, referred to collectively as proteases. The IGF signalling pathway is not only a major player in mammalian statural growth but is also involved in cellular proliferation and survival. Even though growth hormone (GH) is the primary regulator of IGF-I production in many tissues, IGFs are produced almost ubiquitously and circulate at high concentrations in serum mostly bound to IGFPBs. For IGFs to exert their effects through association with IGF1R, their tyrosine kinase cell-surface receptor, they must first dissociate from the complexes formed with IGFBP whose affinities for IGF-I and IGF-II are sometimes higher than those of IGF1R. Thus, receptor-ligand interaction is highly dependent on “free” IGF levels which are tightly regulated by the IGFBPs present in serum and other biological fluids. Therefore, the interaction of IGFs with IGFBPs can prevent untoward IGF effects, such as uncontrolled cellular proliferation or hypoglycaemia. Conversely, disruption of the IGF/IGFBP complex is a probable prerequisite for IGFs to exert their mitogenic and metabolic effects through the IGF receptor.
Dysregulated IGF signalling pathway has emerged as a major player in the pathogeny of numerous malignant tumors as well as in their resistance to chemotherapeutic agents (Samani et al., Endocr. Rev., 2006, 24: 24). Increased activity in this pathway promotes cell proliferation via the activation of the Ras/MAPK/ERK pathway, and counteracts pro-apoptotic signals through the activation of the PI3-kinase signalling pathway. For these reasons, targeting the IGF signalling pathway in order to reduce its activity has become a major challenge of current medical research (Yuen and Macaulay, Expert. Opin. Ther. Targets, 2008, 12: 589-603).
Furthermore, modifying the IGF supply to certain tissues could help control the course of a wide variety of human diseases including dwarfism due to IGF deficiency, type I and type II diabetes, but also degenerative diseases such as myotonic muscular dystrophy (Heatwole et al., Arch. Neurol., 2011, 68: 37-44), amyotrophic lateral sclerosis neurodegeneration (Goberdhan et al., Differentiation, 2003, 71: 375-397) and vasculo-proliferative retinopathies such as those complicating diabetes, prematurity and ageing and even arteriosclerosis. In addition, an acute increase in bio-available IGF may be beneficial to patients suffering from burns, brain or heart ischemia, wasting syndromes and losses of bone mineral density (Clemmons, Nat. Rev. Drug Discov., 2007, 6: 821-833).
The concentrations of IGF-I and IGF-II in the blood are, at least in part, indirectly determined by the levels of IGFBPs. The insulin-like growth factor binding protein 3 (IGFBP-3) is the most abundant IGFBP in blood and has the highest affinity for IGF-I and IGF-II and is, therefore, the main IGF reservoir in the blood stream (Jones and Clemmons, Endocr. Rev., 1995, 16: 3-34). In addition to its role in IGF sequestration and transport, IGFBP-3 may have biological effects of its own. In line with its five IGFBP congeners, IGFBP-3 consists of three domains of roughly equal size of which only the N-terminal and C-terminal domains participate in IGF binding (Sitar et al., Proc. Natl. Acad. Sci. USA, 2006, 103: 13028-13033). The intermediate domain, which is loosely structured, is the target of proteolytic cleavages crucial to some of its functions (Fowlkes et al., Endocrinology, 2004, 145: 620-626). IGFBP-degrading proteases induce the release of IGF, from IGF/IGFBP-3 complexes, making IGF available for biological action. In addition, certain free IGFBPs can also be acted upon by proteases, resulting in reduced affinity for IGFs.
Several approaches have been used to target the IGF signalling pathway including (1) reduction of IGF-1 levels or bioactivity using ligand-specific antibodies (Goya et al., Cancer Res., 2004, 64: 6252-6258) or growth hormone (GH) antagonists (Divisova et al., Breast Cancer Res. Treat., 2006, 98: 315-327) and (2) inhibition of IGF receptor function using (a) receptor-specific antibodies such as the anti-IGF1R antibodies developed by Pfizer (CP-751871—Lacy et al., J. Clin. Oncol., 2008, 26: 3196-3203; Haluska et al., Clin. Cancer Res., 2007, 13: 5834-5840; De Bono et al., Clin. Cancer Res., 2007, 13: 3611-3616), Amgen (AMG479—Tolcher et al., J. Clin. Oncol., 2007, 25: 3002; Sarantopoulos et al., J. Clin. Oncol., 2008, 26: 3583)), Sanofi-Aventis (AVE1642—Tolcher et al., J. Clin. Oncol., 2008, 25: 3582), Imclone (A12—Higano et al., J. Clin. Oncol., 2007, 25: 3505), Merck (MK0646—Hidalgo et al., J. Clin. Oncol., 2008, 26: 3520; Atzori et al., J. Clin. Oncol., 2008, 26: 3519) and Roche (R1507—Rodon et al., J. Clin. Oncol., 2007, 26: 3590) or (b) small-molecule tyrosine kinase inhibitors (Haluska et al., Cancer Res., 2006, 66: 362-371; Ji et al., Mol. Cancer Ther., 2007, 6: 2158-2167; Zimmermann et al., Bioorg. Med. Chem. Lett., 2008, 18: 4075-4080; Mulvihill et al., Bioorg. Med. Chem. Lett., 2008, 16: 1359-1375; Hofmann et al., Drug Discov. Today, 2005, 10:1041-1047; Vasilcanu et al., Oncogene, 2008, 27: 1629-1638).
Administration of recombinant IGF-I (called mecasermin, brand name: Increlex™ by Tercica, Inc.), when indicated, is hampered with undesired side effects such as hypoglycaemia, the short half life of free IGF-I and at the same time reduced efficacy due to endogenous IGFBPs. In an attempt to increase half-life while reducing these side effects of recombinant human IGF-1 (rhIGF-1), an approach consisting of administration of a complex made of equimolar amounts rhIGF-1 and recombinant human IGFBP-3 (rhIGFBP-3) (mecasermin rinfabate, brand name: SomatoKine™ or Iplex™ by Insmed Corp.) has been developed. The efficacy of the rhIGF-1/rhIGFBP-3 complex has been tested in subjects with severe-insulin resistance (Regan et al., J. Clin. Endocrinol. Metab., May 2010, 95: 2113-2122), growth-hormone insensitivity syndrome (Kemp et al., Endocr. & Metabol., 2006, 15: 409-415; Tonella et al., Horm. Res. Paediatr., February 2010, 73: 140-147), type 1 diabetes (Clemmons et al., J. Clin. Endocrin. Metab., 2000, 85: 1518-1524), type 2 diabetes (Clemmons et al., J. Clin. Endocrin. Metab., 2005, 90: 6561-6568), osteoporosis (Boonen et al., Endocrinol. Metab., 2002, 87: 1593-1599), burns (Jeschke et al., Mol. Med., 2002, 8: 238-246), myotonic dystrophy type 1 (Heatwole et al., Arch. Neurol., September 2010), as well as in low birth children (Iniguez et al., Clin. Endocrinol., 2006, 65: 687-392).
These studies are encouraging in that they demonstrate the usefulness of this approach to deliver IGF-I for therapeutic purposes.